Cholesterol Constrains the Antigenic Configuration of the Membrane-Proximal Neutralizing HIV-1 Epitope
- 25 June 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Infectious Diseases
- Vol. 6 (8), 2155-2168
- https://doi.org/10.1021/acsinfecdis.0c00243
Abstract
The envelope glycoprotein (Env) enables HIV-1 cell entry through fusion of host-cell and viral membranes induced by the transmembrane subunit gp41. Antibodies targeting the C-terminal sequence of the membrane-proximal external region (C-MPER) block the fusogenic activity of gp41 and achieve neutralization of divergent HIV-1 strains and isolates. Thus, recreating the structure that generates broadly neutralizing C-MPER antibodies during infection is a major goal in HIV vaccine development. Here, we have reconstituted a peptide termed CpreTM-TMD in a membrane environment. This peptide contains the C-MPER epitope and the minimum TMD residues required for the anchorage of the Env glycoprotein to the viral membrane. In addition, we have used antibody 10E8 variants to gauge the antigenic configuration attained by CpreTM-TMD as a function of the membrane cholesterol content, a functional determinant of the HIV envelope and liposome-based vaccines. Differential binding of the 10E8 variants and the trend of the IgG responses recovered from rabbits immunized with liposome-peptide formulations, suggested that cholesterol may restrict 10E8 accessibility to the C-MPER epitope. Our data ruled out the destabilization of the lipid bilayer architecture in CpreTM-TMD-containing membranes, and pointed to the perturbation of the helical conformation by lipid packing as the cause of the antigenic configuration loss induced by cholesterol. Overall, our results provide additional insights into the structural basis of the Env complex anchoring to membranes, and suggest new approaches to the design of effective immunogens directed against the near pan-neutralizing HIV-1 epitope C-MPER.Keywords
Funding Information
- Medical Research Council (G0902418, MC_UU_12010, MC_UU_12025)
- Ministerio de Ciencia e Innovaci?n (RTI2018-095624-B-C21)
- European Regional Development Fund (RTI2018-095624-B-C21)
- Deutsche Forschungsgemeinschaft (3162113987 ? SFB 1278)
- H2020 Marie Sklodowska-Curie Actions (790012)
- Eusko Jaurlaritza (IT1196-19, POS_2018_1_0066)
- Euskal Herriko Unibertsitatea (DOCREC18/01)
This publication has 69 references indexed in Scilit:
- Neutralizing Epitopes in the Membrane-Proximal External Region of HIV-1 gp41 Are Influenced by the Transmembrane Domain and the Plasma MembraneJournal of Virology, 2012
- Membrane-Proximal External HIV-1 gp41 Motif Adapted for Destabilizing the Highly Rigid Viral EnvelopeBiophysical Journal, 2011
- All-or-None versus Graded: Single-Vesicle Analysis Reveals Lipid Composition Effects on Membrane PermeabilizationBiophysical Journal, 2010
- Epitope specificities of broadly neutralizing plasmas from HIV-1 infected subjectsVaccine, 2010
- Aromatic residues at the edge of the antibody combining site facilitate viral glycoprotein recognition through membrane interactionsProceedings of the National Academy of Sciences of the United States of America, 2010
- Truncation of the Membrane-Spanning Domain of Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Defines Elements Required for Fusion, Incorporation, and InfectivityJournal of Virology, 2009
- Broad Neutralization of Human Immunodeficiency Virus Type 1 Mediated by Plasma Antibodies against the gp41 Membrane Proximal External RegionJournal of Virology, 2009
- In Vivo gp41 Antibodies Targeting the 2F5 Monoclonal Antibody Epitope Mediate Human Immunodeficiency Virus Type 1 Neutralization BreadthJournal of Virology, 2009
- Analysis of Neutralization Specificities in Polyclonal Sera Derived from Human Immunodeficiency Virus Type 1-Infected IndividualsJournal of Virology, 2009
- Bilayers as Protein Solvents: Role of Bilayer Structure and Elastic PropertiesThe Journal of general physiology, 2007